Proinflammatory cytokines and pathogen associated molecular patterns (PAMPs) activate a classical NF-κB signaling pathway. Upon activation there is inducible degradation of specific inhibitors, IκBs, that retain various NF-κB dimers in the cytoplasm (Ghosh et al. (2002) Cell, 109, S81-96). Alternatively, there is an NF-κB signaling pathway induced by IκB Kinase (IKK)α activation of RelB:p52 dimers that induce several chemokine genes (for example lymphotoxin β) needed for organization of secondary lymphoid organs. While the mechanisms of NF-κB activation are well understood (Ghosh et al. (2002) Cell, 109, S81-96), the generation of biological specificity by this complex system is more enigmatic (Pomerantz et al. (2002) Mol Cell, 10, 693-695).
In vivo analysis revealed that IKKα activates an alternative NF-κB pathway based on processing of NF-κB2/p100 and release of RelB:p52 dimers in response to LTα/β trimers (Dejardin et al. (2002) Immunity, 17, 525-535) and other TNF family members (Claudio et al. (2002) Nat Immunol, 3, 958-965; Kayagaki et al. (2002) Immunity, 17, 515-524). This pathway is required for secondary lymphoid organogenesis and induction of genes involved in this process, but has no apparent role in TNFα-induced functions (Dejardin et al. (2002) Immunity, 17, 525-535; Senftleben et al. (2001) Science, 293, 1495-1499). However, the mechanisms by which IKKα regulates cytokine-induced gene expression are obscure and controversial (Israel et al. (2003) Nature, 423, 596-597).
Therefore, it is important to know more about how RelB:p52 dimers are involved in induction of organogenic chemokines and other important regulatory molecules to activation of the alternative pathway for diseases associated with alterations in IKKα activity.